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Why ACC Trials Remain Underpowered

Clinical Trials and Evidence Gaps

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy in which clinical research is constrained by both low incidence and marked biologic and treatment heterogeneity. Within the hierarchy of ACC evidence gaps, underpowered trials are not an isolated methodological flaw but a recurring feature of the field: the limited number of eligible patients affects randomized comparisons, biomarker validation, subgroup analyses, and even the interpretation of routine retrospective cohorts.123

The problem extends beyond rarity alone. ACC studies commonly draw from referral centers, retrospective databases, and small multicenter collaborations that differ in stage distribution, hormone secretion status, pathology review, treatment sequencing, and access to expert surgery or systemic therapy.456 As a result, apparently similar cohorts may not be directly comparable, and observed outcome differences may reflect selection bias, missing data, or inconsistent endpoints as much as true treatment effect.78

This evidence structure has practical consequences across diagnosis, local therapy, systemic treatment, and survivorship research. Much of the literature consists of retrospective series, small prospective studies, reviews, and occasional case reports, which are useful for hypothesis generation but less reliable for establishing comparative efficacy or standardizing care.91011 Consequently, many ACC recommendations remain provisional and are interpreted in the context of multidisciplinary expertise rather than high-certainty trial evidence.

Background and diagnostic context

ACC is uncommon enough that most centers encounter few cases, and clinically important subgroups are smaller still. Localized, recurrent, metastatic, hormonally functional, nonfunctional, adult, and pediatric ACC differ substantially in prognosis, urgency, and treatment goals, yet these groups are often combined to preserve sample size.48 The reliable conclusion is that pooled ACC cohorts often include biologically dissimilar populations; the less reliable assumption is that results apply uniformly across all subgroups.

Referral concentration partly improves consistency of care, but it also introduces selection. Expert centers may disproportionately treat younger, fitter, operable, or more intensively managed patients, which can limit generalizability to broader practice settings.112 Registry and claims analyses may broaden representation, but they often lack detailed endocrine, molecular, surgical, and pathology variables needed to address confounding adequately.6 Clinically, this means both single-center expertise and population-scale datasets provide useful but incomplete views of ACC care.

These background constraints shape the rest of the literature. Questions that would ideally be studied separately by disease state or phenotype are often merged into broader analyses, preserving accrual at the cost of interpretability.

Major drivers of underpowered ACC trials

Small eligible populations and slow accrual

The most direct driver of underpowered ACC trials is the small number of patients eligible for any specific question. Even international efforts may require long recruitment periods to reach modest sample sizes, and pediatric ACC is affected even more severely.1314 This pattern is consistently supported; less certain is whether long accrual windows preserve relevance when staging, supportive care, and treatment standards change over time. The practical implication is that trial completion alone does not guarantee that a result will answer a contemporary clinical question.

Biological and clinical heterogeneity

ACC likely comprises multiple biological subsets, but most studies are too small to test them separately. Differences in stage, resection status, proliferative markers, hormone excess, molecular alterations, and prior treatment exposure may dilute treatment effects and make predictive biomarkers appear inconsistent.151617 What is reliable is that heterogeneity weakens signal detection; what is less reliable is any unvalidated subgroup claim derived from small exploratory datasets. In practice, negative overall results may still obscure benefit in narrow subsets, while positive biomarker findings often remain provisional until external validation.

Nonstandardized workup and treatment pathways

Retrospective series repeatedly describe variation in endocrine testing, pathology reporting, margin assessment, Weiss criteria documentation, mitotane monitoring, radiotherapy use, and systemic therapy sequencing.5718 The existence of this variability is well supported, but the contribution of each individual practice difference to outcomes is often not measurable. Clinically, pooled results may therefore reflect differences in care delivery as much as differences in the intervention under study.

Endpoint and comparator problems

In ACC, overall survival may be influenced by subsequent therapies, repeat surgery, ablation, or crossover treatment, while progression-free survival and response rate may not fully capture delayed benefit, durable stabilization, or patient burden.8 Many studies also lack randomized comparators or well-matched controls, weakening causal inference.419 The practical implication is that endpoint choice matters unusually strongly in ACC, and negative or positive findings should be interpreted in light of the entire treatment pathway rather than a single metric.

Consequences across treatment domains

These methodological constraints become most visible when evidence is applied to major treatment decisions.

Systemic therapy

Mitotane remains central to ACC management, but major questions about the magnitude of benefit, target exposure, duration, and patient selection remain incompletely resolved.1911 EDP-mitotane is widely used in advanced disease, yet retrospective and population-based analyses remain vulnerable to low event counts, treatment selection, and incomplete adjustment for prognostic factors.2021 The reliable conclusion is that these regimens are the best-supported available options; the less reliable conclusion is that their benefit has been defined with high precision across all patient groups.

Novel systemic strategies face the same barriers. Prospective early-phase studies in ACC are feasible, but many have shown limited activity, and translational targets are often supported mainly by preclinical or exploratory evidence.22233 Case reports of unusual responses may identify hypotheses, but they do not establish reproducible efficacy.2425 In practical terms, most nonstandard systemic approaches remain investigational rather than evidence-based alternatives to established care.

Surgery and local therapy

Surgical and local-treatment questions are also difficult to answer definitively. Evidence for adjuvant approaches, radiotherapy for local control, and primary-tumor resection in metastatic disease is dominated by retrospective studies and expert interpretation.92627 Reported survival advantages may partly reflect favorable tumor biology, limited metastatic burden, or referral-center selection rather than the local intervention itself.2827 The practical implication is that aggressive local therapy may be appropriate in selected patients, but routine use cannot be justified by current evidence alone.

Surveillance, recurrence, and disease evolution

Even surveillance-related evidence remains limited. Rare reports of ACC appearing after prolonged observation of lesions initially considered benign highlight imperfections in current risk stratification, but such cases do not show that broader or longer surveillance improves outcomes overall.29303132 What is reliable is that present surveillance frameworks do not eliminate uncertainty; what is not reliable is extrapolating exceptional late presentations into general policy changes for all incidentalomas.

Interpretation pitfalls and clinical implications

Underpowered ACC research increases the risk of both false-negative and false-positive conclusions. Small uncontrolled series may overestimate benefit, whereas a genuinely useful intervention may appear ineffective if the study cannot distinguish modest effect from random variation.333425 This is especially relevant in orphan-drug development, where therapeutic urgency and biologic plausibility may exceed evidentiary strength.19

These uncertainties also contribute to variation between centers. Differences in use of adjuvant mitotane, surgery in advanced disease, treatment sequencing, and pediatric management may reflect unresolved evidence gaps rather than true consensus on equivalent options.3514 For clinical practice, the most dependable implication is that multidisciplinary review and careful patient selection remain essential when the literature does not offer definitive comparative guidance.

Approaches to strengthening the evidence base

Because single institutions rarely have sufficient volume to answer major ACC questions alone, the field increasingly emphasizes international collaboration, shared registries, harmonized definitions, centralized pathology and molecular review, and prospective multicenter infrastructure.131236 These strategies are the most consistently supported response to underpowering, although they cannot fully overcome the underlying rarity of the disease.

Reviews and methodological discussions also suggest that ACC trial design may need to depart from common-cancer models. Proposed approaches include biologically enriched enrollment when justified, clearer accounting for missing data and treatment selection, endpoints that better reflect multimodality care and quality of life, and validation-focused translational research rather than repeated small exploratory analyses.1583 Overall, the literature supports cautious interpretation of current findings and continued development of collaborative research structures capable of producing more reliable ACC evidence.

Included Articles

  • PMID 2569081: A brief early clinical report describes suramin use in five patients with metastatic ACC refractory to mitotane, with mostly absent responses, one transient stabilization, and one temporary complete regression of pulmonary metastases. The authors emphasize serum level monitoring, substantial toxicity concerns, and recommend restricting suramin to carefully planned studies.33
  • PMID 2924693: A single 1989 case report describes near-complete but temporary regression of lung metastases from refractory metastatic ACC with suramin after failure of platinum-based chemotherapy and mitotane, followed by relapse on low-dose maintenance and notable hematologic, coagulation, and renal toxicities. The authors conclude suramin should be limited to controlled studies after conventional therapy failure.34
  • PMID 7946567: In a primary-culture cytotoxicity assay including five ACC samples, 2-chlorodeoxyadenosine showed little or no in vitro activity across solid tumors overall, with ACC represented among the tested solid tumor types. The study frames such assay data as potentially useful for prioritizing diagnoses in early-phase drug evaluation, pending clinical validation.37
  • PMID 10702112: In pediatric androgen-secreting adrenocortical carcinomas, this letter emphasizes major evidence gaps after surgery, notes that histologic features did not reliably correlate with invasion or metastasis, and advocates multicenter collaboration, standardized management, clinical trials, and tumor banking to improve biological understanding and treatment evidence.13
  • PMID 16622753: This case report highlights the absence of established systemic treatment guidelines for metastatic ACC and describes an experimental multimodality approach including TIP chemotherapy, liver-directed therapy, proton irradiation, and reduced-intensity allogeneic stem cell transplantation, with prolonged survival in a single patient.24
  • PMID 17890895: This review examines whether adrenocortical hyperplasia and adenomas are precursor lesions for ACC and concludes that current clinical, chromosomal, and gene-expression data remain insufficient to confirm either multistep progression or de novo carcinoma development. Small sample sizes and limited follow-up are emphasized as major barriers to firm conclusions.38
  • PMID 17901614: This article frames ACC as an orphan malignancy with scarce patient numbers, limited provider experience, and fragmented clinical and epidemiologic data. It argues that a shared registry linking patients, providers, and researchers could reduce evidence gaps and support biomarker research, treatment development, and more efficient data access.1
  • PMID 21559614: In adrenocortical carcinoma, variable P-glycoprotein immunoreactivity did not correlate with broad in vitro resistance to multiple standard cytotoxic agents. These findings suggest that poor chemotherapy responsiveness is driven by other mechanisms and that P-glycoprotein staining is not a useful predictive marker for drug resistance.39
  • PMID 21969107: This review emphasizes that ACC treatment evidence is limited by rarity, retrospective series, heterogeneous regimens, and selection bias. It highlights ongoing randomized trials comparing EDP-mitotane with streptozotocin-mitotane in advanced disease and adjuvant mitotane versus surveillance, while noting unresolved questions about chemotherapy efficacy and radiotherapy benefit.4
  • PMID 21971765: This review summarizes early metronomic chemotherapy experience in advanced ACC, noting possible disease control with gemcitabine plus metronomic fluoropyrimidines in heavily pretreated patients, while combinations with antiangiogenic agents were unsuccessful. It emphasizes unresolved questions about optimal dosing, timing, drug selection, and integration with standard therapy.40
  • PMID 22358232: A cohort study of pediatric and adult adrenocortical tumors found no association between the COL18A1 endostatin p.D104N polymorphism and tumor occurrence, malignant behavior, histopathologic features, recurrence, metastasis, or mortality. The authors note that small sample size and disease heterogeneity may limit interpretation.41
  • PMID 24714084: This review emphasizes major unresolved ACC treatment questions and argues for international collaborative studies, including prospective trials in surgery and adjuvant therapy, better first-line options for metastatic disease, and large multicenter retrospective analyses for radiotherapy and salvage approaches.9
  • PMID 27016977: This discussion emphasizes that ACC evidence is limited by rarity, small retrospective multi-institutional cohorts, inconsistent mitotane level monitoring, and substantial selection bias, making conclusions about adjuvant benefit uncertain. The speakers advocate regionalized multidisciplinary care and prospective randomized trials, while highlighting unmet needs in molecular profiling and novel therapies.5
  • PMID 27335134: This review uses mitotane in advanced adrenocortical carcinoma as an example of orphan-drug evidence limitations, noting approval based largely on uncontrolled retrospective series and post-marketing studies that did not demonstrate a survival benefit. It also highlights the broader failure of post-approval research to close key efficacy and safety gaps in rare diseases.19
  • PMID 27617213: This case report describes a small, localized ACC detected on serial surveillance imaging that was resected promptly yet progressed to widespread metastatic disease within months. It highlights the limited therapeutic window in some ACCs and questions whether current adrenal mass management paradigms reliably improve outcomes through earlier detection.29
  • PMID 28348073: This case report describes an apparently typical small nonsecreting lipid-rich adrenal adenoma that remained stable for 5 years but was followed 14 years later by a 6 cm ACC with metastases and death. It highlights the exceptional uncertainty around whether very rare adenoma-to-ACC transformation can occur and supports that a single case should not overturn surveillance recommendations.30
  • PMID 28400402: This review frames ACC within rare endocrine malignancies for which optimal management is not well defined and guidelines rely largely on retrospective evidence. It highlights growing interest in molecular targeted therapies driven by emerging genomic, epigenomic, and transcriptomic insights, while emphasizing the lack of prospective ACC-specific data.10
  • PMID 29134376: This reply highlights evidence limitations in a national database study of adrenocortical carcinoma, noting substantial missingness for staging, comorbidity, metastasis, and surgical approach variables across NCDB years. The authors justify including a broader 1998-2011 cohort to preserve statistical power despite incomplete variable capture.6
  • PMID 29319480: This single-center Canadian ACC series highlights substantial inconsistency in diagnostic workup, pathology reporting, and treatment patterns over time, with limited use of standardized metabolic evaluation, margin reporting, and Weiss criteria documentation. The authors emphasize that rarity and heterogeneous practice support the need for collaborative prospective and randomized studies.7
  • PMID 30535924: This editorial frames adrenocortical carcinoma as a rare endocrine malignancy in which guideline recommendations often rely on low-quality evidence, small retrospective series, and expert opinion. It emphasizes the need for multicenter consortia, randomized trials when feasible, and publication of confirmatory, contradictory, negative, and hypothesis-generating data.2
  • PMID 31172443: A multicenter phase II trial found no meaningful activity for single-agent AT-101 in advanced ACC, with no RECIST partial responses among the first 21 assessable patients, leading to early closure for futility. The study also highlights the feasibility of prospective ACC trials despite rarity and underscores persistent unmet need for more effective systemic therapies.22
  • PMID 31308928: This case report highlights uncertainty about the long-term malignant potential of adrenal incidentalomas, describing high-grade ACC identified 7 years after an initially benign-appearing nonfunctioning adenoma. The authors argue that current surveillance duration may miss rare late presentations and that better data are needed to determine follow-up length and risk prediction.31
  • PMID 31493273: This letter reports a single heavily pretreated metastatic ACC case with temporary radiographic response and about 12 months of disease control on oral artemisinin, with minimal toxicity. The authors emphasize that efficacy remains uncertain and call for dedicated preclinical and clinical studies in ACC.25
  • PMID 31597261: This review finds that patients with ACC have reduced health-related quality of life compared with the general population, and that chemotherapy plus mitotane can worsen quality of life despite survival benefit. It also highlights major evidence gaps, with very limited ACC-specific data across surgery, radiotherapy, mitotane, hormonal subtypes, and surveillance, and calls for ACC-specific patient-reported outcome tools.35
  • PMID 31777255: This single-center retrospective ACC series highlights major evidence limitations in routine care: heterogeneous use of surgery, adjuvant mitotane, and multiple later-line systemic regimens, with outcomes broadly comparable to prior reports. The authors emphasize that rarity and limited prospective data leave several treatment decisions non-standardized and support greater clinical trial activity.42
  • PMID 33802418: This editorial synthesizes a Special Issue on ACC that highlights progress in prognostic markers, genomics, preclinical therapeutics, adjuvant risk modeling, and systemic treatment assessment, while emphasizing that many findings remain exploratory and require validation. It underscores major unmet needs in recurrence prediction, molecularly guided therapy, and development of improved treatment strategies through collaborative research.15
  • PMID 34522492: This case report highlights an evidence gap in follow-up strategies for indeterminate adrenal incidentalomas, describing ACC that remained radiographically stable for years before late growth and cortisol excess emerged. The article emphasizes limitations of current guideline-based surveillance and the need for better risk stratification to balance early detection against unnecessary imaging and procedures.32
  • PMID 35171248: This letter argues that reported survival benefit from cytoreductive resection of the primary tumor in metastatic ACC is highly vulnerable to selection bias because key prognostic factors, performance status, treatment response, and operative details were not adequately controlled. It emphasizes that routine primary adrenal surgery is not recommended in extensive metastatic disease, though debulking may be considered in highly selected symptomatic or medically refractory hormone-secreting cases.26
  • PMID 35188202: This letter emphasizes that evidence for cytoreductive surgery in stage IV ACC is limited by retrospective design, selection bias, and unmeasured prognostic factors. It argues that prospective randomized trials are desirable but may be difficult because of ACC rarity, heterogeneous behavior, and limited systemic therapy efficacy.28
  • PMID 35869971: This review argues that ACC trial endpoints should extend beyond overall survival to better reflect disease heterogeneity, delayed treatment effects, multimodal care, and patient experience. It highlights current reliance on PFS and response rate, proposes endpoints such as PFS2 and time to chemotherapy for mitotane-based strategies, and emphasizes major evidence gaps in surrogate validation and quality-of-life assessment.8
  • PMID 35966083: This review highlights autophagy modulation as a potential therapeutic avenue in ACC, including mitotane-associated effects, but emphasizes that evidence is largely limited to cell-line studies. It also notes major methodological challenges in interpreting tissue autophagy markers and calls for clinical validation.23
  • PMID 36197701: A large US claims analysis of incidental adrenal masses found that most lesions were managed with surveillance rather than adrenalectomy, while surgery was more common in functional lesions and adrenocortical carcinoma. The study also highlights limited guideline support and low-quality evidence for surgical decision-making in contemporary incidentaloma care.12
  • PMID 36353581: A 24-year single-center retrospective ACC cohort found increasing use of mitotane and multimodality treatment over time, yet recurrence remained frequent after R0 resection across stages and disease-free survival did not clearly improve. The study underscores persistent poor outcomes and the need for prospective ACC studies.18
  • PMID 36358665: This review frames ACC as a rare cancer with persistently poor outcomes because effective systemic therapies remain limited. It emphasizes that mitotane is still the only FDA-approved drug, most novel therapeutic trials have not shown meaningful benefit, and rarity continues to impede progress and define key research gaps.3
  • PMID 38364625: This letter argues that retrospective population-based data were underpowered to judge the survival impact of EDP-M in metastatic ACC because few eligible patients received the regimen and no propensity-matched comparison was performed. It emphasizes that EDP-M remains guideline-backed despite limited efficacy and highlights the need for better evidence and new therapies.20
  • PMID 38554541: A nationwide retrospective analysis in metastatic ACC found no statistically significant overall survival improvement associated with EDP-M implementation, despite numerical benefit in treated patients. The letter emphasizes selection complexity, shared decision making, referral to expert centers, and the need for better predictors of which patients benefit from EDP-M.21
  • PMID 39293544: A physician-patient perspective argues that adjuvant mitotane for ACC remains supported mainly by retrospective data, with the only randomized trial in lower-risk disease showing no significant recurrence-free survival benefit. The article emphasizes substantial toxicity, uncertain target serum levels and duration, and the need for placebo-controlled prospective trials.11
  • PMID 39652308: This systematic review examines primary tumor resection in metastatic ACC and finds that although most retrospective studies reported longer overall survival with surgery, all included studies had high risk of bias with missing surgical indications and baseline selection differences. The evidence supports only individualized consideration rather than firm survival claims.27
  • PMID 39675931: This letter highlights reported associations between ACC recurrence after R0 resection and alterations in WNT, PI3K, cell cycle, and MYC pathways, while emphasizing key evidence limitations including possible lack of multiple-testing correction, TCGA geographic bias, and the need for larger multicenter validation and therapeutic translation.16
  • PMID 39743450: This letter states that retrospective genomic associations between recurrence after R0 ACC resection and WNT, cell-cycle, and PI3K pathway alterations lose significance after multiple-comparison correction, but remain hypothesis-generating candidates for validation in larger prospective cohorts and trials of pathway-directed therapies.17
  • PMID 40149347: An international case-based survey across seven specialized centers found high within-center multidisciplinary consensus but low inter-center agreement on pediatric ACC treatment sequencing, surgical approach, and systemic therapy. The study emphasizes the lack of standardized international pediatric ACC guidance and the need for collaborative harmonization.14
  • PMID 40375480: A bibliometric review of 5507 ACC publications over 1984-2024 found steadily increasing output, major geographic concentration in North America and Europe, and a positive association between multi-institutional coauthorship and citation counts. The analysis argues that international interdisciplinary collaboration is especially important in this rare disease to strengthen research impact and address unmet needs.36

References

Footnotes

  1. Empowering patients and researchers through a common health information registry: a case example of adrenocortical carcinoma patients and researchers.. Stud Health Technol Inform. 2007. PMID: 17901614. Local full text: 17901614.md ↩ ↩2 ↩3 ↩4

  2. Providing Evidence: Step by Step-a Letter from Associate Editor, Tobias Else, MD.. Horm Cancer. 2019. PMID: 30535924. Local full text: 30535924.md ↩ ↩2 ↩3

  3. Bridging the Scientific Gaps to Identify Effective Treatments in Adrenocortical Cancer.. Cancers (Basel). 2022. PMID: 36358665. Local full text: 36358665.md ↩ ↩2 ↩3 ↩4

  4. Therapy of adrenocortical cancer: present and future.. Am J Cancer Res. 2011. PMID: 21969107. Local full text: 21969107.md ↩ ↩2 ↩3 ↩4

  5. Discussion.. J Am Coll Surg. 2016. PMID: 27016977. Local full text: 27016977.md ↩ ↩2 ↩3

  6. Treatment Patterns and Outcomes for Patients with Adrenocortical Carcinoma Associated with Hospital Case Volume in the United States: A Reply.. Ann Surg Oncol. 2017. PMID: 29134376. Local full text: 29134376.md ↩ ↩2 ↩3

  7. The impact of patient-, disease-, and treatment-related factors on survival in patients with adrenocortical carcinoma.. Can Urol Assoc J. 2018. PMID: 29319480. Local full text: 29319480.md ↩ ↩2 ↩3

  8. New endpoints in adrenocortical carcinoma studies: a mini review.. Endocrine. 2022. PMID: 35869971. Local full text: 35869971.md ↩ ↩2 ↩3 ↩4 ↩5

  9. EJE prize 2014: current and evolving treatment options in adrenocortical carcinoma: where do we stand and where do we want to go?. Eur J Endocrinol. 2014. PMID: 24714084. Local full text: 24714084.md ↩ ↩2 ↩3

  10. Molecular targeted therapies in adrenal, pituitary and parathyroid malignancies.. Endocr Relat Cancer. 2017. PMID: 28400402. Local full text: 28400402.md ↩ ↩2

  11. Adrenocortical Carcinoma and the Mitotane Morass: A Physician/Patient Perspective.. Endocr Pract. 2024. PMID: 39293544. Local full text: 39293544.md ↩ ↩2 ↩3

  12. Management of the incidental adrenal mass, continued surveillance versus surgical excision: analysis of US claims data on contemporary socio-demographic predictors and perioperative outcomes.. Minerva Urol Nephrol. 2023. PMID: 36197701. Local full text: 36197701.md ↩ ↩2

  13. Androgen secreting adrenocortical carcinomas.. Arch Dis Child. 2000. PMID: 10702112. Local full text: 10702112.md ↩ ↩2 ↩3

  14. Multidisciplinary Tumor Board Evaluation of Pediatric Patients with Adrenocortical Tumors Across Seven International Centers.. Cancers (Basel). 2025. PMID: 40149347. Local full text: 40149347.md ↩ ↩2 ↩3

  15. Adrenocortical Carcinoma.. Cancers (Basel). 2021. PMID: 33802418. Local full text: 33802418.md ↩ ↩2 ↩3

  16. Letter to the editor on “Identifying genomic signatures of recurrence in adrenocortical carcinoma after R0 resection”.. Surgery. 2025. PMID: 39675931. Local full text: 39675931.md ↩ ↩2

  17. Response to Letter to the editor: “Identifying genomic signatures of recurrence in adrenocortical carcinoma after R0 resection”.. Surgery. 2025. PMID: 39743450. Local full text: 39743450.md ↩ ↩2

  18. Change of treatment modality and outcomes of adrenocortical carcinoma: a retrospective review of single tertiary center experience over 24 years.. Gland Surg. 2022. PMID: 36353581. Local full text: 36353581.md ↩ ↩2

  19. Letting post-marketing bridge the evidence gap: the case of orphan drugs.. BMJ. 2016. PMID: 27335134. Local full text: 27335134.md ↩ ↩2 ↩3 ↩4

  20. Letter re: Impact of EDP-M on survival of patients with metastatic adrenocortical carcinoma: A population-based study.. Eur J Cancer. 2024. PMID: 38364625. Local full text: 38364625.md ↩ ↩2

  21. Response to Letter RE: Impact of EDP-M on survival of patients with metastatic adrenocortical carcinoma: A population-based study.. Eur J Cancer. 2024. PMID: 38554541. Local full text: 38554541.md ↩ ↩2

  22. A phase II study of the orally administered negative enantiomer of gossypol (AT-101), a BH3 mimetic, in patients with advanced adrenal cortical carcinoma.. Invest New Drugs. 2019. PMID: 31172443. Local full text: 31172443.md ↩ ↩2

  23. Modulation of Autophagy in Adrenal Tumors.. Front Endocrinol (Lausanne). 2022. PMID: 35966083. Local full text: 35966083.md ↩ ↩2

  24. Intensive multimodality therapy including paclitaxel and reduced-intensity allogeneic hematopoietic stem cell transplantation in the treatment of adrenal cancer with multiple metastases.. Int J Clin Oncol. 2006. PMID: 16622753. Local full text: 16622753.md ↩ ↩2

  25. Antineoplastic activity of artemisinin in adrenocortical carcinoma.. Endocrine. 2019. PMID: 31493273. Local full text: 31493273.md ↩ ↩2 ↩3

  26. Letter to the Editor From de Ponthaud et al: “Cytoreductive Surgery of the Primary Tumor in Metastatic Adrenocortical Carcinoma: Impact on Patients’ Survival”.. J Clin Endocrinol Metab. 2022. PMID: 35171248. Local full text: 35171248.md ↩ ↩2

  27. Primary tumour resection in metastasised adrenocortical carcinoma.. Endocr Relat Cancer. 2025. PMID: 39652308. Local full text: 39652308.md ↩ ↩2 ↩3

  28. Response to Letter to the Editor From de Ponthaud et al: “Cytoreductive Surgery of the Primary Tumor in Metastatic Adrenocortical Carcinoma: Impact on Patients’ Survival.”.. J Clin Endocrinol Metab. 2022. PMID: 35188202. Local full text: 35188202.md ↩ ↩2

  29. Biology is Destiny: A Case of Adrenocortical Carcinoma Diagnosed and Resected at Inception in a Patient Under Close Surveillance for Lung Cancer.. Urol Case Rep. 2016. PMID: 27617213. Local full text: 27617213.md ↩ ↩2

  30. From benign adrenal incidentaloma to adrenocortical carcinoma: an exceptional random event.. Eur J Endocrinol. 2017. PMID: 28348073. Local full text: 28348073.md ↩ ↩2

  31. Adrenocortical carcinoma arising from an adrenal adenoma in a young adult female.. J Surg Case Rep. 2019. PMID: 31308928. Local full text: 31308928.md ↩ ↩2

  32. An Adrenocortical Carcinoma Evolving After Nine Years of Latency From a Small Adrenal Incidentaloma.. Cureus. 2021. PMID: 34522492. Local full text: 34522492.md ↩ ↩2

  33. Suramin for treatment of adrenocortical carcinoma.. Lancet. 1989. PMID: 2569081. Local full text: 2569081.md ↩ ↩2

  34. [Treatment of metastatic adrenal carcinoma with suramin].. Dtsch Med Wochenschr. 1989. PMID: 2924693. Local full text: 2924693.md ↩ ↩2

  35. Health-Related Quality of Life in Adrenocortical Carcinoma.. Cancers (Basel). 2019. PMID: 31597261. Local full text: 31597261.md ↩ ↩2

  36. Research Landscape on Adrenocortical Carcinoma Over Four Decades.. Int J Urol. 2025. PMID: 40375480. Local full text: 40375480.md ↩ ↩2

  37. In vitro activity of 2-chlorodeoxyadenosine (CdA) in primary cultures of human haematological and solid tumours.. Eur J Cancer. 1994. PMID: 7946567. Local full text: 7946567.md ↩

  38. Precursor lesions of the adrenal gland.. Pathobiology. 2007. PMID: 17890895. Local full text: 17890895.md ↩

  39. Variable p-glycoprotein immunoreactivity unrelated to cytotoxic drug-resistance in-vitro of human adrenocortical carcinoma.. Int J Oncol. 1994. PMID: 21559614. Local full text: 21559614.md ↩

  40. Metronomic therapy concepts in the management of adrenocortical carcinoma.. Horm Cancer. 2011. PMID: 21971765. Local full text: 21971765.md ↩

  41. Genotype analysis of the human endostatin variant p.D104N in benign and malignant adrenocortical tumors.. Clinics (Sao Paulo). 2012. PMID: 22358232. Local full text: 22358232.md ↩

  42. Clinical presentation, treatment modalities and outcome in patients with adrenocortical carcinoma: A single center experience.. Neoplasma. 2020. PMID: 31777255. Local full text: 31777255.md ↩

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